The essential fatty acids (EFAs) are of two types, the n-3 (or omega-3) series derived from alpha-linolenic acid and the n-6 (or omega-6) series derived from linoleic acid. Linoleic acid and alpha-linolenic acid are like vitamins in that they cannot be manufactured in the body and therefore must be provided in the diet. The body can metabolise them along the pathways below and such metabolism is believed to be essential if they are to fulfil their functions. The pathways, sharing it is believed common enzymes, are:
______________________________________ n-6 n-3 ______________________________________ 18:2 delta-9,12(linoleic acid) 18:3 delta-9,12,15(alpha- linolenic acid) .dwnarw. delta-6 desaturase .dwnarw. 18:3 delta-6,9,12(gamma-linolenic 18:4 delta-6,9,12,15 acid) .dwnarw. elongation .dwnarw. 20:3 delta-8,11,14(dihomo-gamma- 20:4 delta-8,11,14,17 linolenic acid) .dwnarw. delta-5 desaturase .dwnarw. 20:4 delta-5,8,11,14(arachidonic 20:5 delta-5,8,11,14,17 acid) .dwnarw. elongation .dwnarw. 22:4 delta-7,10,13,16(adrenic 22:5 delta-7,10,13,16,19 acid) .dwnarw. delta-4 desaturase .dwnarw. 22:5 delta-4,7,10,13,16 22:6 delta-4,7,10,13,16,19 ______________________________________
The pathways are not normally reversible nor, in man, are n-3 and n-6 series acid interconvertible.
The acids, which naturally are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19-docosahexaenoic acid, but numerical designation such as, correspondingly, 18:2 n-6 or 22:6 n-3 is convenient. Initials, for example, DHA for 22:6 n-3 (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid. It was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature is to the alpha-acid.
In the body, the n-3 acids are metabolised preferentially and as a result, in plasma for example, levels of alpha-linolenic acid (18:3 n-3) are low and 18:4 n-3 and 20:4 n-3 are in trace amounts only. In contrast the n-6 acids are normally present in moderate amounts, though gamma-linolenic acid (GLA) is at low levels, being apparently converted to dihomo-gamma-linolenic acid (DGLA) more rapidly than its relatively slow production from linoleic acid. In both series the elongation stages in the metabolic pathways are much more rapid that the desaturations.
Particular significance of the n-6 series acids lies in prostaglandin (PG) synthesis, the outline of which is believed to be as shown in the following diagram: ##STR1##
The broad outline of this pathway is well known, and it brings out clearly that a major function of essential fatty acids is to act as precursors for 1-series PGs formed from DGLA and 2-series PGs formed from arachidonic acid. Further, it has recently been found that the 22:4 n-6 acid produced from arachidonic acid gives rise to a series of homo-2-series PGs, though their importance is as yet unknown.
DGLA is the key substance. GLA is almost completely and very rapidly converted in the body to DLGA and so for practical purposes the oral administration of DGLA and GLA amounts to the same thing. DGLA can be converted to a storage form or to PGs of the 1-series or, through arachidonic acid, to PGs of the 2-series.
Considering dietary requirements, it is well known, for example, that linoleic acid cannot be made by the body and so must be taken in the diet. However, it has been generally thought that the body can metabolise linoleic acid to all the other n-6 acids and therefore that provided linoleic acid intake is adequate, no lack of the other n-6 acids will be found.
In previous patent applications (for example Published European patent application No. A 0 003 407, U.S. Pat. No. 4,273,763; Published European patent application No. A 0 004 770, U.S. Pat. No. 4,309,415; Published European patent application No. 0 019 423, U.S. Pat. No. 4,388,324) it has, however, been pointed out that the first enzyme in the pathway, the delta-6 desaturase which, for example, converts linoleic acid to GLA, is not fully effective in a variety of conditions. The administration of GLA or DGLA or both has been suggested and has been successful in treating a variety of clinical conditions. Australian Pat. No. 524106 relates, inter alia, to the treatment of diabetes mellitus with GLA and/or DGLA and a material, for example, zinc influencing the 1-series/2-series PG balance in the body in favour of 1-series PGs.
In the above patent applications attention is primarily paid to the function of essential fatty acids in prostaglandin metabolism and in particular to their role in securing a proper balance between 1-series and 2-series PGs. Attention is primarily paid therefore to the n-6 acids.
The applicants are, however, becoming increasingly aware of the significance of the essential fatty acids in themselves as set out above. Considerable general interest has been shown in them in recent years, primarily in the acids of the n-6 series both as such and in relation to prostaglandin metabolism, but also in the acids of the n-3 series. The n-6 acids in particular are believed to be required in the body for the structure of membranes in and around cells, maintaining normal flexibility, fluidity and permeability of such membranes and the n-3 acids are unlikely to have a merely passive role.
Diabetes mellitus is a common condition in which there is either a deficiency of insulin or a resistance to the action of insulin. This produces severe abnormalities in metabolism, especially of carbohydrates. These abnormalities can lead to coma and death. The disease can be treated by insulin or in milder cases by diet and oral drugs. However, while these measures are relatively successful in correcting the acute problems of carbohydrate metabolism, it is increasingly recognised that the survivors in the long term suffer a range of damage to large and small blood vessels, to the eyes, kidneys and nerves. The nerve damage, known a diabetic neuropathy, leads to a range of abnormalities. The reasons for these long term complications are not understood but the applicants believe they lie at least in part in diabetics being unable to perform the normal reaction of the delta-6 desaturase. On this basis diabetics may be expected to benefit from the administration of GLA or one of its further metabolites and/or of 18:4 n-3 or one of its further metabolites, so by-passing the defective step. The applicants have found that the administration of GLA is indeed beneficial to diabetics suffering from diabetic neuropathy.
An improvement in methods for measuring the function of fine nerves in humans is discussed in G. A. Jamal et al., "An Improved Automated Method for the Measurement of Thermal Thresholds", J. Neurol Neurosurg Psych 48: 354-60 (1985). Using this test, many diabetics show defective nerve function. A group of 16 diabetics with such defective nerve function has been studied and its members have been treated for three months with either evening primrose oil containing GLA, or a placebo containing no GLA. After three months the group treated with evening primrose oil showed a highly significant improvement in peripheral nerve function as compared with the placebo group. The GLA appears to reverse already established abnormalities in diabetics, and it is also to be expected to be effective in preventing development of such abnormalities.
It is also anticipated that the further metabolites of GLA will improve diabetic neuropathy in diabetic patients, and since the postulated delta-6 desaturase abnormality will also affect the n-3 acids, it is to be expected that 18:4 n-3 and its higher metabolites will contribute to or enhance the therapeutic and preventative effects of GLA and indeed have benefit alone.
The success of GLA in the treatment of diabetic neuropathy strongly suggests that it is also likely to be of value in the prevention and treatment of other long term complications of diabetes, including those in the cardiovascular system, the kidneys and the eyes.